Abstract 11614: A Hyaluronidase Inhibitor Prevents the Development of Experimental Abdominal Aortic Aneurysm by Interfering Interplay Between Low Molecular Weight Hyarulonan and Cd44
Background: Abdominal aortic aneurysm (AAA) is a common disease characterized by inflammation and extracellular matrix (ECM) degradation in vessel wall. Hyaluronic acid (HA) is one of major ECM components in aortic vessel. Recently, small fragmented HA by degradation has been shown to play an important role in inflammation through CD44, a principal receptor of HA. We examined whether HA fragmentation contribute to the development of AAA in mice.
Methods: For induction of AAA, we applied CaCl2 to infrarenal aorta of wild-type (WT) mice and then fed diet with or without L-ascorbic acid 6-hexadecanoate (Vcpal), a hyaluronidase inhibitor (10mg/day). CD44-deficient mice were also treated with CaCl2 for induction of AAA.
Results: We first assessed HA metabolism in AAA lesion. One week after application of CaCl2, the increased expression of hyaluronidase 1 and the decreased expression of hyaluronic acid synthase 2 were observed in WT mice. Electrophoresis also showed the increased in smaller size HA in AAA. To evaluate the role of HA degradation in the AAA formation, Vcpal was given to the experimental AAA model. The enlargement of aortic diameter in Vcpal-treated WT mice (n=8) was significantly less than that in non-treated WT mice (n=10) (15%±24% vs. 53%±12%, p<0.01). In vitro experiment showed that Vcpal inhibited the HA degradation by hyaluronidase dose-dependently. Those results suggest that HA fragmentation could be involved in the development of AAA. Next, we evaluated the interaction between HA fragment and CD44. The enlargement of experimental AAA in CD44-deficient mice (n=8) was significantly smaller than that in WT mice (n=10) (12%±13% vs. 53%±12%, p<0.01). The elevated expression of MMP-2, -9, and MCP-1 and recruited macrophages in WT mice were significantly ameliorated in CD44-deficient mice. Finally we demonstrated that low-molecular-weight HA, but not high-molecular-weight HA stimulated MMP-9 production in peritoneal macrophages, and this induction was abolished in CD44-deficient mice.
Conclusion: HA fragmentation contributes to the pathogenesis of the development of AAA in mice through CD44. The hyaluronidase inhibiton, may have therapeutic potential for AAA..
- © 2011 by American Heart Association, Inc.